Cannabinoid receptor ligands and uses thereof

• US 20040077650A1
• Filed: 10/06/2003
• Published: 04/22/2004
• Est. Priority Date: 10/18/2002
• Status: Abandoned Application

• Current Assignee: Pfizer Inc.
• Original Assignee: Pfizer Inc.
• Inventors: Dow, Robert L.
• Application Number:
  US10/679,878
• Publication Number:
  US 20040077650A1
• Time in Patent Office: Days
• US Class Current: 514/242
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 25/08 Antiepileptics; Anticonvulsants
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/24 Antidepressants
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 25/30 for treating abuse or dependence
• CPC Class Codes: A61P 25/32 Alcohol-abuse
• CPC Class Codes: A61P 25/36 Opioid-abuse
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 403/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 405/14 containing three or more hetero rings

Abstract

Compounds of Formula (I) that act as cannabinoid receptor ligands and their uses in the treatment of diseases linked to the modulation of the cannabinoid receptors in animals are described herein.

Claims

1. A compound of Formula (I)

2. The compound of claim 1 where R⁵ and R⁶ are each independently an aryl or a heteroaryl, where said aryl and said heteroaryl are substituted with one to three substituents selected from the group consisting of halo, (C₁-C₄)alkoxy, (C₁-C₄)alkyl, halo-substituted(C₁-C₄)alkyl and cyano.

3. The compound of claim 2 wherein R⁵ is 2,4-dihalophenyl or 2-halophenyl and R⁶ is 4-halophenyl or 2-(C₁-C₆)alkoxypyridin-5-yl;

a pharmaceutically acceptable salt thereof, a prodrug of said compound or said salt, or a solvate or hydrate of said compound, said salt or said prodrug.

4. The compound of claim 3 wherein R⁵ is 2,4-dichlorophenyl or 2-chlorophenyl and R⁶ is 4-chlorophenyl or 2-methoxypyridin-5-yl;

a pharmaceutically acceptable salt thereof, a prodrug of said compound or said salt, or a solvate or hydrate of said compound, said salt or said prodrug.

5. The compound of claim 1 selected from the group consisting of

5-(4-chloro-phenyl)-3-(5-cyclohexyl-1H-imidazol-2-yl)-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole;

5-(4-chloro-phenyl)-3-(2-cyclohexyl-3H-imidazol-4-yl )-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole;

5-(4-chloro-phenyl)-1-(2,4-dichloro-phenyl)-4-methyl-3-[1 -(1-methyl-1-phenyl-ethyl)-1H-imidazol-4-yl]-1H-pyrazole;

5-(4-chloro-phenyl)-1-(2-chloro-phenyl)-4-methyl-3-[1-(1-phenyl-ethyl)-1H-imidazol-4-yl]-1H-pyrazole;

5-(4-chloro-phenyl)-1-(2-fluoro-phenyl)-4-methyl-3-[1-(1-methyl-1-phenyl-ethyl)-1H-imidazol-4-yl]-1H-pyrazole;

5-(4-chloro-phenyl)-1-(2-chloro-phenyl)-3-[1-(2,2-dimethyl-tetrahydro-pyran-4-yl)-1H-imidazol-4-yl]-4-methyl-1H-pyrazole;

5-{2-(2,4-dichloro-phenyl)-4-methyl-5-[1 -(1-methyl-1-phenyl-ethyl)-1H-imidazol-4-yl]-2H-pyrazol-3-yl}-2-methoxy-pyridine; and

1-(2-chloro-phenyl)-5-(4-chloro-phenyl)-4-methyl-3-[1-(1-methyl-1-phenyl-ethyl)-1H-imidazol-4-yl]-1H-pyrazole;

a pharmaceutically acceptable salt thereof or a solvate or hydrate of said compound or said salt.

13. A pharmaceutical composition comprising (1) a compound of claim 1, a pharmaceutically acceptable salt thereof, a prodrug of said compound or said salt, or a solvate or hydrate of said compound, said salt or said prodrug;

and (2) a pharmaceutically acceptable excipient, diluent, or carrier.

14. The pharmaceutical composition of claim 13 wherein said compound of claim 1 is a compound where R⁵ is 2,4-dichlorophenyl or 2-chlorophenyl and R⁶ is 4-chlorophenyl or 2-methoxypyridin-5-yl;

a pharmaceutically acceptable salt thereof, a prodrug of said compound or said salt, or a solvate or hydrate of said compound, said salt or said prodrug.

15. The pharmaceutical composition of claim 13 or 14 further comprising a nicotine partial agonist, an opioid antagonist, a dopaminergic agent, an attention deficit disorder agent, or an anti-obesity agent.

16. The composition of claim 15 wherein said anti-obesity agent is selected from the group consisting of an apo-B/MTP inhibitor, an 11β

-hydroxy steroid dehydrogenase-1 inhibitor, peptide YY_3-36 or an analog thereof, a MCR-4 agonist, a CCK-A agonist, a monoamine reuptake inhibitor, a sympathomimetic agent, a β

₃ adrenergic receptor agonist, a dopamine agonist, a melanocyte-stimulating hormone receptor analog, a 5-HT2c receptor agonist, a melanin concentrating hormone antagonist, leptin, a leptin analog, a leptin receptor agonist, a galanin antagonist, a lipase inhibitor, a bombesin agonist, a neuropeptide-Y receptor antagonist, a thyromimetic agent, dehydroepiandrosterone or analog thereof, a glucocorticoid receptor antagonist, an orexin receptor antagonist, a glucagon-like peptide-1 receptor agonist, a ciliary neurotrophic factor, a human agouti-related protein antagonist, a ghrelin receptor antagonist, a histamine 3 receptor antagonist or inverse agonist, and a neuromedin U receptor agonist.

21. A method for treating a disease, condition or disorder modulated by a cannabinoid receptor antagonist in animals comprising the step of administering to an animal in need of such treatment a therapeutically effective amount of a compound of claim 1, a pharmaceutically acceptable salt thereof, a prodrug of said compound or said salt, or a solvate or hydrate of said compound, said salt or said prodrug.

22. The method of claim 18 wherein said compound of claim 1 is a compound where R⁵ is 2,4-dichlorophenyl or 2-chlorophenyl and R⁶ is 4-chlorophenyl or 2-methoxypyridin-5-yl;

a pharmaceutically acceptable salt thereof, a prodrug of said compound or said salt, or a solvate or hydrate of said compound, said salt or said prodrug.

23. The method of claim 21 or 22 wherein said disease, condition or disorder modulated by a cannabinoid receptor antagonist is selected from the group consisting of eating disorders, weight loss or control, obesity, depression, atypical depression, bipolar disorders, psychoses, schizophrenia, behavioral addictions, suppression of reward-related behaviors, substance abuse, addictive disorders, impulsivity, alcoholism, tobacco abuse, dementia, sexual dysfunction in males, seizure disorders, epilepsy, gastrointestinal disorders, attention deficit disorder, Parkinson'"'"'s disease, and type II diabetes.

24. The method of claim 23 wherein said disease, condition or disorder modulated by a cannabinoid receptor antagonist is obesity, alcoholism, attention deficit disorder, or tobacco abuse.

25. The method of claim 21 wherein said compound of claim 1 is administered in combination with a nicotine partial agonist, an opioid antagonist, a dopaminergic agent, an attention deficit disorder agent, or an anti-obesity agent.

26. The method of claim 25 wherein said anti-obesity agent is selected from the group consisting of an apo-B/MTP inhibitor, an IIβ

-hydroxy steroid dehydrogenase-1 inhibitor, peptide YY_3-36 or an analog thereof, a MCR-4 agonist, a CCK-A agonist, a monoamine reuptake inhibitor, a sympathomimetic agent, a β

₃ adrenergic receptor agonist, a dopamine agonist, a melanocyte-stimulating hormone receptor analog, a 5-HT2c receptor agonist, a melanin concentrating hormone antagonist, leptin, a leptin analog, a leptin receptor agonist, a galanin antagonist, a lipase inhibitor, a bombesin agonist, a neuropeptide-Y receptor antagonist, a thyromimetic agent, dehydroepiandrosterone or analog thereof, a glucocorticoid receptor antagonist, an orexin receptor antagonist, a glucagon-like peptide-1 receptor agonist, a ciliary neurotrophic factor, a human agouti-related protein antagonist, a ghrelin receptor antagonist, a histamine 3 receptor antagonist or inverse agonist, and a neuromedin U receptor agonist.

6. A compound having Formula (IA) or (IB)

7. The compound of claim 6 where R⁵ and R⁶ are each independently an aryl or a heteroaryl, where said aryl and said heteroaryl are substituted with one to three substituents selected from the group consisting of halo, (C₁-C₄)alkoxy, (C₁-C₄)alkyl, halo-substituted(C₁-C₄)alkyl and cyano.

8. The compound of claim 7 having Formula (IA);

a pharmaceutically acceptable salt thereof, a prodrug of said compound or said salt, or a solvate or hydrate of said compound, said salt or said prodrug.

17. A pharmaceutical composition comprising (1) a compound of claim 6, a pharmaceutically acceptable salt thereof, a prodrug of said compound or said salt, or a solvate or hydrate of said compound, said salt or said prodrug;

and (2) a pharmaceutically acceptable excipient, diluent, or carrier.

18. The pharmaceutical composition of claim 17 wherein said compound of claim 6 is a compound where R⁵ is 2,4-dichlorophenyl or 2-chlorophenyl and R⁶ is 4-chlorophenyl or 2-methoxypyridin-5-yl;

a pharmaceutically acceptable salt thereof, a prodrug of said compound or said salt, or a solvate or hydrate of said compound, said salt or said prodrug.

19. The pharmaceutical composition of claim 17 or 18 further comprising a nicotine partial agonist, opioid antagonist, a dopaminergic agent, an attention deficit disorder agent, or an anti-obesity agent.

20. The composition of claim 19 wherein said anti-obesity agent is selected from the group consisting of an apo-B/MTP inhibitor, an 11β

-hydroxy steroid dehydrogenase-1 inhibitor, peptide YY_3-36 or an analog thereof, a MCR-4 agonist, a CCK-A agonist, a monoamine reuptake inhibitor, a sympathomimetic agent, a β

₃ adrenergic receptor agonist, a dopamine agonist, a melanocyte-stimulating hormone receptor analog, a 5-HT2c receptor agonist, a melanin concentrating hormone antagonist, leptin, a leptin analog, a leptin receptor agonist, a galanin antagonist, a lipase inhibitor, a bombesin agonist, a neuropeptide-Y receptor antagonist, a thyromimetic agent, dehydroepiandrosterone or analog thereof, a glucocorticoid receptor antagonist, an orexin receptor antagonist, a glucagon-like peptide-1 receptor agonist, a ciliary neurotrophic factor, a human agouti-related protein antagonist, a ghrelin receptor antagonist, a histamine 3 receptor antagonist or inverse agonist, and a neuromedin U receptor agonist.

27. A method for treating a disease, condition or disorder modulated by a cannabinoid receptor antagonist in animals comprising the step of administering to an animal in need of such treatment a therapeutically effective amount of a compound of claim 6, a pharmaceutically acceptable salt thereof, a prodrug of said compound or said salt, or a solvate or hydrate of said compound, said salt or said prodrug.

28. The method of claim 27 wherein said compound of claim 6 is a compound where R⁵ is 2,4-dichlorophenyl or 2-chlorophenyl and R⁶ is 4-chlorophenyl or 2-methoxypyridin-5-yl;

a pharmaceutically acceptable salt thereof, a prodrug of said compound or said salt, or a solvate or hydrate of said compound, said salt or said prodrug.

29. The method of claim 27 or 28 said disease, condition or disorder modulated by a cannabinoid receptor antagonist is selected from the group consisting of eating disorders, weight loss or control, obesity, depression, atypical depression, bipolar disorders, psychoses, schizophrenia, behavioral addictions, suppression of reward-related behaviors, substance abuse, addictive disorders, impulsivity, alcoholism, tobacco abuse, dementia, sexual dysfunction in males, seizure disorders, epilepsy, gastrointestinal disorders, attention deficit disorder, Parkinson'"'"'s disease, and type II diabetes.

30. The method of claim 29 wherein said disease, condition or disorder modulated by a cannabinoid receptor antagonist is obesity, alcoholism, attention deficit disorder, or tobacco abuse.

31. The method of claim 27 wherein said compound of claim 6 is administered in combination with a nicotine partial agonist, an opioid antagonist, a dopaminergic agent, an attention deficit disorder agent, or an anti-obesity agent.

32. The method of claim 31 wherein said anti-obesity agent is selected from the group consisting of an apo-B/MTP inhibitor, an 11β

-hydroxy steroid dehydrogenase-1 inhibitor, peptide YY_3-36 or an analog thereof, a MCR-4 agonist, a CCK-A agonist, a monoamine reuptake inhibitor, a sympathomimetic agent, a 3 adrenergic receptor agonist, a dopamine agonist, a melanocyte-stimulating hormone receptor analog, a 5-HT2c receptor agonist, a melanin concentrating hormone antagonist, leptin, a leptin analog, a leptin receptor agonist, a galanin antagonist, a lipase inhibitor, a bombesin agonist, a neuropeptide-Y receptor antagonist, a thyromimetic agent, dehydroepiandrosterone or analog thereof, a glucocorticoid receptor antagonist, an orexin receptor antagonist, a glucagon-like peptide-1 receptor agonist, a ciliary neurotrophic factor, a human agouti-related protein antagonist, a ghrelin receptor antagonist, a histamine 3 receptor antagonist or inverse agonist, and a neuromedin U receptor agonist.

9. A compound having Formula (IC) or (ID)

10. The compound of claim 9 where R⁵ and R⁶ are each independently an aryl or a heteroaryl, where said aryl and said heteroaryl are substituted with one to three substituents selected from the group consisting of halo, (C₁-C₄)alkoxy, (C₁-C₄)alkyl, halo-substituted(C₁-C₄)alkyl and cyano.

11. The compound of claim 7, 8, or 10 wherein R⁵ is 2,4-dihalophenyl or 2-halophenyl and R⁶ is 4-halophenyl or 2-(C₁-C₆)alkoxypyrid in-5-yl;

a pharmaceutically acceptable salt thereof, a prodrug of said compound or said salt, or a solvate or hydrate of said compound, said salt or said prodrug.

12. The compound of claim 11 wherein R⁵ is 2,4-dichlorophenyl or 2-chlorophenyl and R⁶ is 4-chlorophenyl;

a pharmaceutically acceptable salt thereof, a prodrug of said compound or said salt, or a solvate or hydrate of said compound, said salt or said prodrug.